FLK1 (VEGFR2), a receptor tyrosine kinase, is a critical component for blood cell and vessel formation as evidenced by knockout studies. FLK1 continues to play an important role in postnatal and pathological angiogenesis. Therefore, understanding molecular mechanisms of Flk1 expression is essential for delineating the pathways involved in vessel formation as well as postnatal angiogenesis. We have demonstrated that the transcription factor ER71 (also known as ETV2) is a critical regulator of FLK1 and thereby it is essential for generation of vascular endothelial cells. Deficiency in Er71 leads to embryonic lethality with a complete absence of vascular structures and blood cells. We also showed that ER71 functions to directly regulate Flk1, indicating the important role of the ER71-FLK1 axis in pathophysiological angiogenesis. However, the mechanisms by which ER71 regulates Flk1 expression and neovascularization remain largely unexplored. Our preliminary studies provide compelling evidence showing its potent and unexpected functions in the mechanism of vascular endothelial cell generation and revascularization in the adult. With our new data, we hypothesize that the interaction between ER71 and OVOL2 is essential for optimal FLK1+ cell generation and revascularization. Additionally, we will test the hypothesis that ER71 regulates FLK1+ cell generation through miR126-Spread1-MAPK signaling. Finally, we will test the hypothesis that reactivation of ER71 following ischemic injury promotes neovascularization through Flk1 expression and thus activates the VEGF-FLK1 signaling pathway. Upon completed, our findings will provide a new and detailed insight into the role of ER71 in vascular endothelial cell generation and revascularization in the adult, which can lead to the development of new therapeutic strategies for cardiovascular diseases.